Project Summary Recent work suggests that disrupted sleep is a bi-directional feature in the pathological progression of Alzheimer?s disease. Human studies have focused on ?-amyloid (A?) accumulation, which has been shown to predict subjective and objective declines in sleep quality. It remains unknown whether tau protein, the other primary pathological feature of Alzheimer?s disease, contributes to sleep disruption. In rodent models, aggregated tau predicts abnormalities in non-rapid eye movement (NREM) sleep physiology. This finding is functionally relevant, due to the known role of NREM sleep oscillations in supporting long-term memory consolidation. Specifically, the strength of coordinated coupling of three NREM sleep oscillations (slow waves, spindles, and sharp-wave ripples), which occurs within the human medial temporal lobe (MTL), has been demonstrated to predict overnight memory retention. MTL is known to be one of the first brain regions to accumulate tau pathology, before the onset of Alzheimer?s disease symptomology. Given this anatomical overlap, we hypothesize that MTL tau burden will predict disrupted coordination of NREM sleep oscillations in cognitively normal older adults at risk for Alzheimer?s disease. We further predict that this tau-induced disruption of oscillatory coupling will be associated with impaired long-term memory consolidation. By combining (i) in vivo brain imaging of tau pathology (18F-AV1451 PET), (ii) overnight high-density EEG, (iii) weeklong wristwatch actigraphy measures of sleep, and (iv) sensitive measures of memory consolidation, this proposal aims to characterize associations between tau and sleep physiology, and their impact on hippocampus-dependent memory in the context of preclinical Alzheimer?s disease. Aim 1 will determine whether early tau accumulation in MTL is associated with the disruption of NREM sleep oscillations, and if this disruption results in failed memory consolidation. Aim 2 seeks to determine whether wristwatch actigraphy measures of sleep quality across multiple nights may serve as a sensitive and specific marker of tau burden. By elucidating the relationship between tau pathology and multiple measures of sleep, these experiments may provide important preliminary data for developing sleep-based therapies targeting Alzheimer?s disease prevention and treatment.